The impact of chronic endometritis on reproductive outcome

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1 INFERTILITY The impact of chronic endometritis on reproductive outcome Jenneke C. Kasius, M.D., a Human M. Fatemi, M.D., Ph.D., d Claire Bourgain, M.D., Ph.D., e Daisy M. D. S. Sie-Go, M.D., Ph.D., b Rene J. C. Eijkemans, Ph.D., c Bart C. Fauser, M.D., Ph.D., a Paul Devroey, M.D., Ph.D., d and Frank J. M. Broekmans, M.D., Ph.D. a a Department of Reproductive Medicine and Gynecology, b Department of Pathology, and c Julius Center for Health Sciences and Primary Care, University Medical Center, Utrecht, the Netherlands; d Department of Reproductive Medicine and e Department of Pathology, Academic Hospital at the Dutch-Speaking Brussels Free University, Brussels, Belgium Objective: To assess the prevalence of chronic endometritis and the impact on the fertility of asymptomatic patients indicated for in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) treatment. Design: In the context of a randomized controlled trial, a hysteroscopy-guided endometrial biopsy was obtained and histologically examined. The live birth rate (including spontaneous pregnancies) after initiation of IVF/ICSI treatment of patients diagnosed with chronic endometritis was compared with the live birth rate of a randomly selected matched control group of patients without endometritis. Setting: Two tertiary infertility care units. Patient(s): A total of 678 asymptomatic infertile women with a normal transvaginal ultrasound (TVS) who underwent diagnostic hysteroscopy before a first IVF/ICSI treatment cycle. Intervention(s): Hysteroscopy guided endometrial biopsy. Main outcome measure(s): The prevalence of chronic endometritis and the live birth rate (including spontaneous pregnancies) within 3 years after initiation of the randomized controlled trial. Result(s): The prevalence of chronic endometritis in the 606 patients with an adequate biopsy was 2.8%. The cumulative live birth rate (including spontaneous pregnancies) did not significantly differ between patients with or without endometritis: 76% versus 54%. Also, the clinical pregnancy rate per embryo transfer was not significantly different (hazard ratio 1.456, 95% confidence interval ). Conclusion(s): Chronic endometritis can be rarely diagnosed in a population of asymptomatic infertile patients with a normal TVS before a first IVF/ICSI treatment. Moreover, the reproductive outcome after initiation of IVF/ICSI was not found to be negatively affected by chronic endometritis. In conclusion, the clinical implication of chronic endometritis seems minimal. (Fertil Steril Ò 2011;96: Ó2011 by American Society for Reproductive Medicine.) Key Words: Chronic endometritis, endometrial pathology, infertility, IVF, ICSI, plasma cell The implantation rate per in vitro fertilization (IVF) embryo transfer generally does not exceed 30% per cycle (1). Factors that affect chances of embryo implantation are related either to the embryo Received February 8, 2011; revised September 4, 2011; accepted September 23, 2011; published online October 22, J.C.K. has nothing to disclose. H.M.F. is a member of the external advisory board for MSD/Organon Pharmaceuticals, for which he receives no monetary compensation. C.B. has nothing to disclose. D.M.D.S.S.-G. has nothing to disclose. R.J.C.E. has nothing to disclose. B.C.F. has received fees and grant support from the following companies (in alphabetical order); Andromed, Ardana, Ferring, Genovum, Glycotope, Merck Serono, Organon, Pantharei Bioscience, Philips, PregLem, Schering, Schering Plough, Serono, and Wyeth. P.D. has received fees and grant support from the following companies (in alphabetical order); Anecova, Besins, Ferring, Merck Serono, and Schering-Plough. F.J.M.B. is a member of the external advisory board for Ferring Pharmaceuticals, Hoofddorp, the Netherlands, for which he receives no monetary compensation. Reprint requests: Jenneke C. Kasius, M.D., Gynecology and Obstetrics, MC Utrecht, Heidelberglaan 100, Postbus GA, Utrecht, the Netherlands ( j.c.kasius@umcutrecht.nl). itself or to the receptivity of the endometrium. Endometrial polyps, submucus myomas, adhesions, and septa are all thought to have a negative impact on the uterine environment and therefore to interfere with fertility (2, 3). Also less distinct endometrial pathology (such as altered hormonal status or inflammation) is thought to cause impaired endometrial receptivity resulting in infertility (4). Chronic endometritis is a subtle condition and therefore difficult to diagnose. Clinically, the condition is rarely suspected, because chronic endometritis is usually asymptomatic. Also at hysteroscopy, with direct visibility of the endometrial surface, the diagnosis often remains doubtful or unnoticed (5). A hysteroscopy-guided endometrial biopsy is assumed to be the method of choice to ensure the integrity of the uterine cavity before IVF (6). Although infiltration of the endometrium by lymphocytes and eosinophils is associated with chronic endometritis, the diagnosis is ultimately based on the presence of plasma cells in the endometrial stroma (7 10). The search for plasma cells may be hampered by many factors such as inadequate staining, preservation of the endometrial tissue, or /$36.00 Fertility and Sterility â Vol. 96, No. 6, December doi: /j.fertnstert Copyright ª2011 American Society for Reproductive Medicine, Published by Elsevier Inc.

2 mimicking of plasma cells by plasmacytoid stroma cells (7, 8, 11). Therefore, histologic diagnosis also is difficult to make. The significance of chronic endometritis in infertility has not been fully assessed yet. The prevalence reported in previous published articles varies greatly. Depending on the patient population and biopsy method, the prevalence of chronic endometritis has been reported to be between 0.2% and 46% (5, 12 15). Moreover, literature regarding the possible impact of chronic endometritis on fertility is scarce (16). To the best of our knowledge, the only available evidence resides in a prospective study among patients with symptomatic endometritis and a retrospective chart review among patients with recurrent IVF failure (15, 17). Both studies failed to detect a clear association between chronic endometritis and reproductive outcome. Therefore, the aim of the present study was to identify the prevalence of chronic endometritis in a population of asymptomatic patients with normal findings at transvaginal ultrasound (TVS) before a first IVF/intracytoplasmic sperm injection (ICSI) cycle, based on the histologic diagnosis of a hysteroscopy guided biopsy. In addition, the impact of chronic endometritis on fertility was assessed by comparing the reproductive outcome between the group of patients with and that without chronic endometritis. MATERIALS AND METHODS The data for this study were collected in the context of the TEA (Treatment Efficacy of Uterine Abnormalities) trial, ClinicalTrial.gov registration no. NCT (18). The aim of this randomized controlled trial was to clarify whether diagnosis and treatment of unsuspected intrauterine abnormalities by office hysteroscopy would affect the reproductive outcome of the subsequent IVF/ICSI treatment cycles. The Institutional Review Board of the two participating centers approved this study. Informed consents were obtained. Participants The investigated population consisted of infertile patients who visited the Academic Hospital at the Dutch-Speaking Brussels Free University (AZ-VUB) and the University Medical Center Utrecht (UMC-U). From June 2007 to September 2008, subsequent asymptomatic patients <43 years old were allocated for the TEA trial and scheduled for office hysteroscopy before a first IVF/ICSI treatment. Inclusion was limited to patients without abnormalities at TVS and no earlier hysteroscopy examination. Hysteroscopy and Endometrial Biopsy The hysteroscopies were scheduled in the follicular phase of the menstrual cycle (days 3 15). On the day of the examination, before the hysteroscopy, a single dose of antibiotic prophylaxis was prescribed at the UMC-U: 625 mg amoxicillin/clavulanate potassium orally (Augmentin; GlaxoSmithKline) and 200 mg doxycyclin orally (Vibramycin; Pfizer). The hysteroscopies were performed on an outpatient basis with the use of a 5-mm (outer diameter) continuous-flow Bettocchi hysteroscope (St opler Medical Instruments, Utrecht, the Netherlands & Olympus Belgium N.V., Aartselaar, Belgium). A vaginoscopic approach was used. The endocervical canal, uterine cavity, tubal orifices, and endometrium were inspected methodically and the findings recorded. In case predefined abnormalities were detected (i.e., endometrial polyps, myoma, adhesions, or septa), randomization for treatment versus no treatment was performed. Despite previous permission, some patients withdrew from randomization and applied for definite treatment. During the procedure, an endometrial biopsy was obtained from the uterine fundus with the use of grasping forceps (Karl Storz Endoscopie; UMC-U) or a Pipelle de Cornier (Laboratoire CCD; AZ-VUB) under local anesthesia. Histology Examination The endometrial biopsies were placed in a fixative of 4% phosphate-buffered formaldehyde and processed routinely. At each research hospital, one pathologist specialized in endometrial pathology examined the endometrial samples, initially making use of solely hematoxylin-eosin stained (HE) tissue specimens. Additional staining by immunohistochemical markers CD20, CD79a, and/or CD138 was provided only in case the diagnosis was doubtful. For plasma cells, CD138 antibody clone B-B4, batch 605 (Serotec), was used at 1:1,000 dilution. For plasma cells and B-lymphocytes, CD79a antibody clone JCB117, batch 2791 (Dako), was used at 1:200 dilution. For B-lymphocytes, CD20 antibody clone L26, batch 083 (Dako), the DAKO was used at 1:400 dilution. For all antibodies, antigen retrieval in citrate buffer was applied, and staining was done with the Bond-Max autostainer (Leica). The histologic examination consisted of classification based on the Kurman criteria and the presence or absence of inflammatory cells, such as plasma cells, lymphocytes, neutrophils, etc. (19). Finally, the examining pathologists of each research hospital recorded the corresponding diagnosis: no inflammation, possibly endometritis, evident (sub)acute endometritis, or evident chronic endometritis. Fertility Treatment Besides the antibiotic prophylaxis, at the UMC-U no other antibiotic treatment was administered. At the AZ-VUB the gynecologist decided whether antibiotic treatment was indicated in patients diagnosed with endometritis. Treatment consisted of 400 mg/d ofloxacin orally for 5 days for the patient and her partner. One to 3 months after the hysteroscopy and biopsy, standard IVF/ICSI treatment was started. Recombinant FSH or hmg, long (day 21) agonist protocol (100 mg leuprolide/triptorelin) or day 6 GnRH antagonist protocol (0.25 mg/d ganirelix/cetrorelix) was used. Final oocyte maturation was obtained by administration of 10,000 IU hcg (Pregnyl) as soon as R3 follicles >16 mm were present. Oocyte retrieval was carried out 36 hours after hcg administration. A maximum of two good quality embryos were transferred, generally 4 days after oocyte retrieval. Luteal phase supplementation consisting of 600 mg natural micronized progesterone in three separate doses (2 3/d 100 mg utrogestan/progestan) was started 1 day after oocyte retrieval and continued until 7 weeks gestation if pregnancy was achieved. Unused good-quality embryos could be cryopreserved and transfered in the next treatment cycle. The ongoing pregnancies resulting in a live birth after treatment cycles with fresh or cryopreserved embryos performed within 3 years after the start of the TEA trial were used for analysis. Also, the spontaneous pregnancies resulting in a live birth were taken into account. Statistical Analysis The chi-square test, Fisher exact test, Student t test, and multinominal logistic regression were used to analyze the differences in patients characteristics of the group with and without endometritis. To analyze the impact of the histologic diagnoses on the chance to conceive, the group of patients with chronic endometritis (case group) was compared with a control group. For each case, four control subjects out of the patients without endometritis were randomly selected, matched for the research hospital and day of menstrual cycle on which the biopsy was performed. Survival analysis (Kaplan-Meier) was performed to analyze the difference in pregnancy rate between the case and control subjects over time, expressed as number of embryo transfers. Cox regression was used to analyze the size of the effect. A P value of <.05 was considered to be statistically significant. All statistical analyses were performed in SPSS version 15.1 software. RESULTS From June 2007 to September 2008, 678 patients underwent office hysteroscopy. Adequate histologic examination could be performed on the endometrial samples of 606 patients. Causes for inadequate histologic examination are shown in Figure 1. No significant clinical differences were found between the groups with and without histologic examination. Histology Findings Based on solely the hematoxylin-eosin stained endometrial samples, evident chronic endometritis was diagnosed in 15 patients and focal (sub)acute endometritis in four. Additional staining with 1452 Kasius et al. Chronic endometritis and fertility Vol. 96, No. 6, December 2011

3 FIGURE 1 Flow chart illustrating the selection of cases used for the analysis of the IVF treatment outcome. Cases diagnosed with chronic endometritis were matched with a sample of randomly selected patients not diagnosed with chronic endometritis. Matching was performed by research center and day of menstrual cycle on which the endometrial biopsy was obtained. a The trial Treatment Efficacy of unsuspected uterine Abnormalities on subsequent in vitro fertilization (IVF) or intra cytoplasmic sperm injection (ICSI) treatment (register number: NCT ); b Most patients did not start IVF/ICSI treatment due to personal reasons. One patient did not start because of spontaneous pregnancy resulting in a live birth; c Including 3 patients who had a spontaneous pregnancy resulting in a live birth (of whom one did not undergo IVF/ICSI treatment) and 4 patients, who had an early miscarriage before the live birth; d Including 11 patients who had an early miscarriage and did not become pregnant afterwards and one patient, who had a preterm delivery at 22 weeks gestation; e The final outcome after IVF/ICSI remained unknown. After a sonography at 8 weeks gestation - which showed an intact intrauterine twin pregnancy- no record was kept. a CD marker confirmed the diagnosis of chronic endometritis in three patients. Moreover, it revealed chronic endometritis in two additional patients. The diagnosis remained doubtful in two cases. Overall, in the group of 606 patients with adequate histopathologic examination, the observed prevalence of possibly endometritis, evident (sub)acute endometritis, or evident chronic endometritis was 0.3%, 0.7%, and 2.8%, respectively (Fig. 1). Patient Characteristics Between the 17 cases with evident chronic endometritis (2.8%) and the rest of the 606 patients with adequate histologic examination, univariate analysis showed significant differences for female age and other intrauterine abnormalities found at hysteroscopy (Table 1). Yet multivariate analysis confirmed the significant difference only for presence of uterine abnormalities. More intrauterine abnormalities were detected in the group with chronic endometritis (35% vs. 11%), mostly endometrial polyps (P¼.009; odds ratio 4.03, 95% confidence interval [CI] ). Reproductive Outcome The group investigated for fertility outcome consisted of 17 case subjects and 68 control subjects without chronic endometritis. Of those 85 patients, nine patients (11%) did not start treatment, one because of spontaneous pregnancy resulting in a live birth. A live birth after IVF/ICSI treatment occurred in 47 patients (58%). Two patients had a spontaneous pregnancy during IVF/ICSI treatment. Twenty-six patients (31%) did not become pregnant. Thus, the live birth rate (including spontaneous pregnancies) was 50 out of 85 patients (59%; Table 2). The live birth rate (including spontaneous pregnancies) of the case subjects compared with the control subjects was 76% (13/17) versus 54% (37/68). This difference was not significantly different (P¼.11). Taking into account the number of IVF/ICSI embryo transfers to obtain pregnancy, no significant difference was found between the groups with and without chronic endometritis (Kaplan-Meier curve; Fig. 2). Cox regression showed that the difference in cumulative pregnancy rate in consecutive embryo transfers was not significantly different (hazard ratio 1.456, 95% CI ; P¼.2). Fertility and Sterility â 1453

4 1454 Kasius et al. Chronic endometritis and fertility Vol. 96, No. 6, December 2011 TABLE 1 Patient characteristics of the IVF/ICSI cases that underwent hysteroscopy guided endometrial biopsy which was histological examined, listed according to the presence or absence of chronic endometritis. Variables Group with chronic endometritis (n [ 17) Group without chronic endometritis (n [ 589) Significance, univariate analysis P value Significance, multivariate analysis P value Age, y d.195 Duration of subfertility, y a d BMI, kg/m d TMC d Cycle day d Other uterine cavity 6 (35%) 64 (11%).007 e.009 g,h abnormalities present at screening hysteroscopy Cause of infertility.88 f Idiopathic 8 (47%) 241 (41%) Andrologic factor b 7 (41%) 265 (45%) Subfertile female c 2 (12%) 83 (14%) Tubal pathology 1 (6%) 65 (11%) 1.00 e Infertility woman.99 f Primary 11 (65%) 382 (65%) Secondary 6 (35%) 206 (35%) Note: Values are expressed as mean SD or n (%). BMI ¼ body mass index; TMC ¼ total motile count. a Duration of attempts to become pregnant, calculated in cases of secondary infertility from the last ongoing pregnancy. b Defined as TMC (semen volume [ml] spermatozoa concentration [10 9 /ml]) grade A and B spermatozoa motility [%]) < c Due to tubal pathology (including endometriosis grade III and IV), anovulation, or cervix factor. d Student t test. e Fisher exact test. f Chi-square test. g Corrected for age using multinomial logistic regression. h Odds ratio 4.03, 95% CI

5 TABLE 2 IVF/ICSI results of the patients with chronic endometritis (case subjects) compared with control subjects. Variables Case (n [ 17) Control (n [ 68) Significance No. of started cycles a b Fresh cycles b Cryocycles b No. of embryo transfers b No. of embryos transferred per cycle b Live birth 13 (76%) 37 (54%).11 c Note: The control group consisted of a randomly selected sample of patients without endometritis, matched for the research hospital and day of menstrual cycle on which the biopsy was performed. Values are expressed as mean SD or n (%). a Number of started cycles within 3 years after the start of the initial trial (TEA trial, registration no. NCT ) or until a live birth was obtained or treatment was stopped. b Student t test. c Chi-square test. DISCUSSION Chronic endometritis is known to be a subtle condition that is hard to diagnose. Moreover, the influence of endometritis on fertility has not been fully assessed. In the present study, histologic examination of hysteroscopy-guided endometrial biopsies of infertile patients before a first IVF/ICSI treatment cycle revealed chronic endometritis in 2.8%. In the rather small group of patients diagnosed with endometritis, the live birth rate (including spontaneous pregnancies) within 3 years after initiation of IVF/ICSI treatment was not significantly different that that in patients without endometritis. One of the possible study limitations that should be considered is the use of an enriched sample. For each of the 17 cases with evident chronic endometritis, four control subjects without chronic endometritis were randomly selected. This may have affected the study results. However, it concerned a matched random selection, and additional analysis with correction for possible confounders (female age, duration of infertility, and presence of intrauterine abnormalities) did not change our study outcome. Also, the small patient population could be interpreted as a study weakness. Because this study was performed as part of the TEA trial, post hoc power analysis was done. Considering the number of included patients, this study would have 80% power to pick up a difference in live birth rate for patients without and with endometritis of 51% versus 88%, resepectively, instead of 51% versus 76%. More important is the hazard ratio on cumulative cycles with the 95% CI of The lower boundary of indicates that the chance lowering effect of endometritis will maximally be a 23% reduction. A good condition of the uterine cavity is essential for successful reproduction. Implantation concerns a process of physiologic inflammation, involving inflammatory mediators, such as leukocytes, cyto- and chemokines, and other endometrial factors (4). The presence of high concentrations of endotoxins, components of gramnegative bacteria, is said to induce a reaction of T H 1 inflammatory cells. T H 1 cells may predispose a hostile endometrial environment and thereby cause implantation failure, spontaneous abortion, or premature labour (20). Endometritis is also considered to be an inflammatory reaction. In contrast to acute endometritis, in chronic endometritis, usually no causal pathogen can be identified (21). Along with the precise etiology of chronic endometritis, the impact on female fertility also is unclear. The prevalence varies between 0.2% and 46%, depending on the biopsy method (blind vs. hysteroscopy-guided) and the investigated infertile patient population (5, 12 15). The present study observed a prevalence of 2.8%, which seems to be in line with the literature, because asymptomatic patients indicated for IVF/ICSI and were investigated. The current literature on the impact of chronic endometritis on fertility consists of two studies. In a population of patients suspected of pelvic inflammatory disease, the pregnancy rate and infertile status of the 356 patients with endometritis did not significantly differ from the pregnancy rate of the 258 patients without endometritis (17). Moreover, among patients with recurrent IVF failure, the FIGURE 2 Survival curve showing the cumulative live birth rate in consecutive embryo cycles for the cases with endometritis compared with those without endometritis, including spontaneous pregnancies resulting in a live birth (control). Fertility and Sterility â 1455

6 ongoing pregnancy rate was similar between the 10 patients with and the 23 patients without endometritis (15). The present study found a live birth rate (including spontaneous pregnancies) of 76% versus 54% for patients with and without chronic endometritis, respectively. The difference was not significant, though the trend of a benefit for patients with chronic endometritis is remarkable. A positive effect of chronic endometritis on fertility has not been described in the literature. Possible explanations for the observed difference in live birth rate could be related to the variation in patient characteristics. First, patients with chronic endometritis more frequently had endometrial polyps. This is a previously reported association, which would unlikely lead to an increase in pregnancy rate (3, 14). Second, prescription of antibiotic treatment was not standardized. However, the effect of antibiotics on chronic endometritis is questionable, because usually no causal pathogen can be identified (21). Third, additional analysis showed a coincidental significant difference between the randomly selected matched control group (n ¼ 68) and the other patients an adequate histopathology examination and without endometritis and (n ¼ 521). The women of the control group were on average 2 years older and suffered 0.5 year less from infertility. Yet, besides the presence of intrauterine abnormalities, the patient characteristics did not significantly differ between the case and control subjects. Moreover, correction for possible confounders did not change the study results. Finally, the presence of plasma cells, the diagnostic criterion for chronic endometritis, has also been reported in women with endometrial atrophy (22, 23). Patients with endometrial atrophy could hypothetically experience more benefit from fertility treatment compared with patients without atrophy, because follicular stimulation also increases endometrial thickness. Still, based on the present study and previously published literature, chronic endometritis has no proven association with infertility (15, 17, 18). Moreover, the effect of antibiotic treatment on nonspecific chronic endometrial inflammation is disputable. Routine performance of a hysteroscopy and guided endometrial biopsy to detect chronic endometritis therefore should not be recommended for daily clinical practice. A randomized controlled trial should be performed to find out whether detection and treatment of chronic endometritis before the start of fertility treatment would indeed optimize fertility outcome. 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